Genetic studies, both association studies and more recently genome wide association studies (GWAS), have identified a large number of DNA variants that potentially confer risk for the development of atopy, asthma and COPD. However, in the majority of these studies the functional variant has not been identified. This largely reflets the fact that, in most cases, the polymorphism(s) identified do not alter the structure of the proteins encoded by genes located in these regions; rather the variants are generally found in non-coding DNA. While these regions often include sequences that could play an important role in regulation of gene expression, including promoters, enhancers or insulator regions, limited tools are currently available to assess the importance of these DNA variations in determining the expression of a given gene during normal development and, perhaps more importantly, in determining the impact of these variations on risk for disease, disease progression and/or the response of the patient to specific therapeutic intervention(s). Furthermore, in most cases it is clear that DNA variants at multiple loci, together with environmental factors, determine risk for disease: these interactions remain particularly difficult to define. In this application we propose to test the hypothesis that mouse models can be developed for testing the impact of disease associated non-coding DNA variants. These mouse models will allow testing of risk associated haplotypes as well as provide a means of resolving the contribution of an individual DNA variation on gene expression. The impact of the change in gene regulation conferred by the risk associated haplotype or individual variant can be evaluated in combination with environmental factors and also in combination with disease associated DNA variants at other unlinked loci.